The long-term objectives are to develop histamine (HA) H3 receptor agonists for therapeutic utility. Phase I chemistry studies targeted the development of chiral heterocyclic H3 agonists. GT-2203 has been identified as the active enantiomeric form of a potent, selective H3 receptor agonist. Several in vitro and in vivo studies have characterized GT-2203 as a potent H3 agonist. Further evidence has demonstrated that GT-2203 is effective in myocardial ischemia models. Specific Aims (year 1) are to (1) synthesize GT-2203 and selected analogs for expanded in vitro and in vivo testing, (2) determine in vitro and in vivo HA receptor selectivity and pharmacodynamic profiles, (3) establish inhibitory effects of the H3 agonists on NE release from guinea pig cardiac synaptosomes (4) characterize the efficacy the lead candidate in a guinea pig cardiac ischemia model and (5) determine receptor selectivity profile for lead candidate. Specific Aims (year 2) involve safety studies for the lead H3 agonist. These include (6) establishing pharmacokinetic parameters for the lead candidate (7) establishing general cardiovascular, respiratory and GI parameters (8) mutagenicity (9) tissue distribution (10) drug metabolism and (11) long-term oral toxicological testing of the H3 agonist. PROPOSED COMMERCIAL APPLICATIONS: A selective HA H3 agonist, GT-2203, has been identified. These studies would further establish the use and safety of the H3 agonist and provide for development.